granulomatosis with polyangiitis; Wegener's granulomatosis
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Introduction
Granulomatous vasculitis of the upper & lower respiratory tract with glomerulonephritis.
Etiology
- unknown
- hypersensitivity to exogenous or endogenous antigens has been suggested
- antecedent infection has been suggested
- Mycoplasma
- Bartonella henselae (Cat stratch disease)
- cytomegalovirus (CMV)
- Varicella-zoster
- genetic factors
Epidemiology
- age of onset
- mean age: 40 years
- occurs at any age
- rarely occurs before adolescence
- male:female ratio 2:1
- rarely occurs in blacks
- prevalence: 3 per 100,000 in USA
- disease exacerbations may occur
- during winter months
- with pregnancy
Pathology
- necrotizing vasculitis of small arteries & veins
- infiltration & obliteration of small arteries & veins by a granulomatous inflammatory process
- both arterioles & venules are affected
- formation of intra & extravascular granulomas
- histopathology
- fibrinoid necrosis of the vessel wall
- infiltration with neutrophils, lymphocytes & monocytes
- multinucleated giant cells
- granuloma formation
- lung
- multiple bilateral cavitary infiltrates
- necrotizing granulomatous vasculitis
- obstruction with atelectasis may be present
- sinuses & nasopharynx
- inflammation
- necrosis with nasal septal perforation
- granulomas
- vasculitis may be present
- renal
- focal segmental glomerulonephritis in early stages
- may evolve into rapidly-progressive crescentic glomerulonephritis
- granuloma formation rarely seen on renal biopsy
- immune complex deposition?
- cardiac
- any organ may show granulomas &/or vasculitis
- large areas of necrosis (geographic necrosis)
- atopy[5]
Genetics
- 6-fold increased risk with PiiZZ variant of alpha-1 antitrypsin gene
Clinical manifestations
E*
- ear/nose/throat (73-92%)
- sinusitis
- otitis media (recurrent), hearing loss, ear pain
- subglottic stenosis (16%)
- oral lesions & ulcerations of the larynx & trachea
- epistaxis
- nasal pain
- nasal crusting
- chondritis of ears & nose
- chronic rhinosinusitis & nasal polyposis[19]
- nasal septal perforation & ulceration of the vomer bone leading to bony destruction of the orbital wall[23] & 'saddle nose' deformity (image)[18][19]
- inflammation of the salivary glands[5]
L*
- lung (85-90%)
- hemoptysis
- pleuritis
- cough
- dyspnea
- intrapulmonary alveolar hemorrhage
- tracheal collapse[5]
K*
- kidney: pauci-immune glomerulonephritis (77%)
S*
- skin: (13-46%)
other
- eyes (1-52%)
- conjunctivitis
- dacryocystitis
- lacrimal gland enlargement
- scleritis, episceritis
- proptosis
- eye pain
- visual loss & double vision
- retinal lesions, retinal vasculitis
- corneal lesions
- iritis
- dacryadenitis
- retro-orbital pseudotumor
- musculoskeletal (32-67%)
- cardiac: pericarditis (2-6%)
- endocrine: hyperthyroidism (1-3%)
- neurologic (23%)
- general
- fever (19-46%)
- weight loss (15-35%)
- malaise
- gingival hyperplasia, strawberry gingivitis rare (image)[15]
- anterior cervical lymphadenopathy with bilateral submandibular lymphadenopathy[11]
* ELKS mneumonic
Laboratory
- anti-neutrophil cytoplasmic Ab (cANCA)
- c or central type cANCA in serum (anti serine-proteinase-3 Ab)[5]
- distinguish from pANCA in serum
- cANCAs are markers of active disease (90% sensitivity)
- not predictive of disease activity[7]
- cANCA may play a role in pathology of the disease
- 70% cANCA positive[21]
- elevated erythrocyte sedimentation rate (ESR)
- often > 100 mm/hour
- complete blood count (CBC) with differential
- mild leukocytosis
- thrombocytosis may be present
- normocytic, normochromic anemia
- associated eosinophilia[5] is NOT characteristic
- basic metabolic panel may show elevated serum creatinine
- hypergammaglobulinemia, mild
- generally increased serum IgA
- serum IgG increase also seen
- circulating immune complexes
- positive rheumatoid factor (mildly elevated)
- serum complement levels are normal
- urinalysis (abnormal in 80% of patients)
- biopsy
- unnecessary in patients with classic presentation & positive cANCA[5]
- reserve biopsy for atypical presentation[5]
- renal biopsy
- biopsy of lung or nasal mucosa
- open lung biopsy may be more likely to provide sufficient tissue for diagnosis than nasal or sinus mucosa biopsy or transbronchial lung biopsy[5]
- skin biopsy[5]
- see ARUP consult[9]
Radiology
- chest X-ray (65% abnormal)
- pulmonary infiltrates (63%)
- pulmonary nodules (31%)
- solitary nodules in 30-40%
- cavitation in 30%
- 55% unilateral, 5% bilateral
- lobar consolidation
- pleural effusions
- computed tomography of thorax is more sensitive than plain radiographs
- hilar adenopathy alone is inconsistent with Wegener's granulomatosis
- CT of head:
- opacification of the paranasal sinuses
- nasal septal perforation[19] (image)
Complications
- massive pulmonary alveolar hemorrhage
- tracheobronchial stenosis (15%), generally benign
- propensity to venous thromboembolism[8]
- malignancy secondary to cyclophosphamide therapy
- 33-fold increased incidence of bladder cancer[5][14]
- 11-fold increased incidence of lymphoma
- overall cancer incidence increases 2-fold
- the most common causes of death shift with time[16]
- in 1st year: acute vasculitis (85% 1 year survival)
- years 1-5: cardiovascular disease (73% 5 year survival)
- years 5-10: malignancy (53% 10 year survival)[16]
Management
- untreated disease is fatal within a few months
- combination therapy for induction
- rituximab 375 mg/m2/week (4 doses) in combination with glucocorticoids preferred induction for severe disease[20]
- methotrexate in combination with glucocorticoid preferred induction for less severe disease[20]
- historical induction
- plasmapheresis[5]
- intravenous methylprednisolone
- prednisone 1 mg/kg PO QD for 4 weeks followed by slow taper, subsequent conversion to alternate day therapy for 6-9 months
- cyclophosphamide
- 2 mg/kg/day PO for one year after induction of remission
- monthly cyclophosphamide is less toxic, but also less effective
- response in 90%, complete remission in 75% of patients
- 50% of patients with relapses
- rituximab may be used instead of cyclophosphamide[5]
- high-dose glucocorticoids + cyclophosphamide for 6 months[5]
- rituximab, low-dose cyclophosphamide, plus prednisone[19]
- maintenance therapy
- methotrexate
- start 0.3 mg/kg (max 15 mg) q week
- increase 2.5 mg q week up to 20-25 mg q week
- mycophenolate rather than methotrexate[5]
- azathioprine 1-2 mg/kg/day:
- use in conjunction with prednisone as needed[5]
- rituximab in combination with glucocorticoids preferred vs cyclophosphamide[5]
- methotrexate
- rituximab superior to cyclophosphamide for replapse
- relapse of disease may be associated with viral infection or bacterial infection
- respiratory infection, especially with Staphylococcus aureus
- incidence of Pneumocystis carinii is 6%
- relapse of disease may be associated with viral infection or bacterial infection
- prophylactic sulfa drugs: sulfonamide (Bactrim), dapsone
- Bactrim DS 1 tab QD
- large airway stenosis
- bronchoscopic dilatation
- YAG-laser treatment
- silicone airway stent
More general terms
More specific terms
References
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1674-6
- ↑ Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 270
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 1914-17
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 35, 781-82, 847-48
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1307
- ↑ 7.0 7.1 Finkielman JD et al, Antiproteinase 3 antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis Ann Intern Med 2007, 147:611 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17975183
- ↑ 8.0 8.1 Khasnis A and Langford CA. Update on vasculitis. J Allergy Clin Immunol 2009 Jun; 123:1226. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19501230
- ↑ 9.0 9.1 ARUP Consult: Granulomatosis with Polyangiitis - GPA The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/granulomatosis-polyangiitis
- ↑ Holle JU, Laudien M, Gross WL. Clinical manifestations and treatment of Wegener's granulomatosis. Rheum Dis Clin North Am. 2010 Aug;36(3):507-26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20688247
- ↑ 11.0 11.1 Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ Al bshabshe AA, Al-Khalidy H, Omer HA et al Pulmonary renal syndrome associated with Wegener's granulomatosis: a case report and review of literature. Clin Exp Nephrol. 2010 Feb;14(1):80-4. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19730971
- ↑ Lutalo PM, D'Cruz DP. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). J Autoimmun. 2014 Feb-Mar;48-49:94-8 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24485158
- ↑ 14.0 14.1 Talar-Williams C, Hijazi YM, Walther MM et al Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996 Mar 1;124(5):477-84. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8602705
- ↑ 15.0 15.1 Ghiasi M. Strawberry Gingivitis in Granulomatosis with Polyangiitis. N Engl J Med 2017; 377:2073. Nov 23, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29166230 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMicm1706987
- ↑ 16.0 16.1 16.2 Walsh N. Mortality Risks Shift in Granulomatosis with Polyangiitis. Main causes evolve from active vasculitis initially to wide range of complications. MedPage Today. May 03, 2018 https://www.medpagetoday.com/meetingcoverage/bsr/72683
Pearce F, et al Mortality in granulomatosis with polyangiitis: a population- based case control study. British Society for Rheumatology (BSR) 2018; abstract O22 - ↑ Comarmond C, Cacoub P. Granulomatosis with polyangiitis (Wegener): clinical aspects and treatment. Autoimmun Rev. 2014 Nov;13(11):1121-5. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25149391
- ↑ 18.0 18.1 Bello F, Fagni F. Nasal Deformity in Granulomatosis with Polyangiitis. Engl J Med 2020; 382:951. March 5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32130816 https://www.nejm.org/doi/full/10.1056/NEJMicm1909658
- ↑ 19.0 19.1 19.2 19.3 19.4 Zonozi R, Niles JL Images in Clinical Medicine, Sunken Nose. N Engl J Med 2021. April 3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33830712 https://www.nejm.org/doi/full/10.1056/NEJMicm2031387
- ↑ 20.0 20.1 20.2 Chung SA, Langford CA, Maz M et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2021 Aug; 73:1366-1383. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34235894 https://onlinelibrary.wiley.com/doi/10.1002/art.41773
- ↑ 21.0 21.1 NEJM Knowledge+ Rheumatology
- ↑ 22.0 22.1 Fillingim SE, Artz C, Rambhatla P. Images in Dermatology. Granulomatosis With Polyangiitis Presenting With Strawberry Gums. JAMA Dermatol. 2023;159(5):554 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36884226 https://jamanetwork.com/journals/jamadermatology/fullarticle/2801912
- ↑ 23.0 23.1 23.2 NEJM Knowledge+ Allergy/Immunology
Patient information
granulomatosis with polyangiitis (Wegener's granulomatosis) patient information